The Arizona bark scorpion (Centruroides exilicauda) and the striped bark scorpion (C. vittatus) produce neurotoxins that selectively bind voltage-gated ion channels in excitable membranes of nerve and muscle, producing hyper-excitability of the nervous and neuromuscular systems. Southern grasshopper mice (Onychomys torridus) and Mearns' grasshopper mice (O. arenicola) are voracious predators of scorpions in U.S. deserts. Southern and Mearns' grasshopper mice demonstrate physiological resistance to bark scorpion venom. Variability in venom resistance among grasshopper mice populations co-varies with geographic patterns of bark scorpion sympatry and allopatry. Electrophysiological assays show that ion channels in the nerve and muscle of grasshopper mice are insensitive to scorpion neurotoxins. The purpose of the proposed project is to determine the molecular genetic basis of ion channel insensitivity in resistant mice, to characterize the molecular variation underlying phenotypic differences in resistance levels among their populations, and to assess patterns of selection on genes involved in toxin resistance. Ion channel encoding genes will be examined for structural and functional changes that impart insensitivity to toxins.